Gelatinase inhibitors and use thereof

Abstract

New gelatinase inhibitors, processes for their preparation, pharmaceutical compositions comprising them, and their use in therapy and/or prophylaxis of conditions wherein inhibition of gelatinases is useful such as epilepsy, schizophrenia, Alzheimer disease, autism (in particular associated to fragile X syndrome), mental retardation, mood disorders such as bipolar disorders, depression, vascular diseases such as ischemic stroke and atherosclerosis, inflammatory diseases such as multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease, drug addiction, neuropathic pain, lung diseases such as asthma and chronic obstructive pulmonary disease, cancer and sepsis.

The invention claimed is: 
     
       1. A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         AA 1  is either absent or represents an amino acid selected from the group consisting of N-methyl-phenylalanine, N-methyl-tryptophan, N-methyl-tyrosine and N-methyl-isoleucine, 
         AA 2  is either absent or represents an amino acid selected from the group consisting of N-methyl-phenylalanine, N-methyl-alanine, N-methyl-β-alanine and N-methyl-leucine, 
         G is a linear or branched alkylene comprising from 1 to 10 carbon atoms wherein one or more non-vicinal methylene moieties (—CH 2 —) are optionally replaced by corresponding oxygen atoms (—O—), 
         R 1  is selected from the group consisting of hydrogen and phenyl, 
         R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen and fluorine, 
         R 5  and R 6  are independently selected from the group consisting of hydrogen and fluorine, 
         or a salt thereof. 
       
     
     
       2. The compound according to  claim 1 , wherein AA 1  and AA 2  are absent. 
     
     
       3. The compound according to  claim 1 , wherein G is selected from the group consisting of —CH 2 —, —(CH 2 ) 3 —, —(CH 2 ) 5 —, —CH 2 —CH(CH 3 )—CH 2 —, —(CH 2 ) 7 —, —CH 2 —CH 2 —CH 2 —CH(CH 2 —CH 2 —CH 3 )—, —O—(CH 2 ) 3 —, —(CH 2 ) 13 — and —CH 2 —O—(CH 2 ) 2 —O—CH 2 —. 
     
     
       4. The compound according to  claim 3 , wherein R 1 -G is selected from the group consisting of CH 3 —(CH 2 ) 2 —, CH 3 —CH(CH 3 )—CH 2 —, phenyl-O—(CH 2 ) 3 —, CH 3 —(CH 2 ) 6 —, CH 3 —(CH 2 ) 4 — and CH 3 —CH 2 —CH 2 —CH(CH 3 —CH 2 —CH 3 )—. 
     
     
       5. The compound according to  claim 1 , wherein one of R 2 , R 3  and R 4  is hydrogen. 
     
     
       6. The compound according to  claim 5 , wherein one of R 2 , R 3  and R 4  is hydrogen and the other two are fluorine atoms. 
     
     
       7. The compound according to  claim 6 , wherein the phenyl group substituted by R 2 , R 3  and R 4  is a 3,5-difluorophenyl. 
     
     
       8. The compound according to  claim 1 , wherein R 5  and R 6  are both hydrogen. 
     
     
       9. The compound according to  claim 1  of formula: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
       10. The compound according to  claim 1  selected from the group consisting of:
 (2S)-1-acetyl-N-[(1S)-1-[[(1S)-3-[(4-fluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-N-methyl-pyrrolidine-2-carboxamide 
 (2S)-1-acetyl-N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-N-methyl-pyrrolidine-2-carboxamide 
 (2S)—N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-1-hexanoyl-N-methyl-pyrrolidine-2-carboxamide 
 (2S)-1-butanoyl-N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-N-methyl-pyrrolidine-2-carboxamide 
 (2S)—N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-N-methyl-1-(3-methylbutanoyl)pyrrolidine-2-carboxamide 
 (2S)—N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-N-methyl-1-octanoyl-pyrrolidine-2-carboxamide 
 (2S)—N-[(1S,2S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-4,4-difluoro-1-hexanoyl-N-methyl-pyrrolidine-2-carboxamide 
 (2S)—N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-N-methyl-1-(2-propylpentanoyl)pyrrolidine-2-carboxamide 
 (2S)—N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-N-methyl-1-(4-phenoxybutanoyl)pyrrolidine-2-carboxamide 
 (2S)—N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-4,4-difluoro-N-methyl-1-(4-phenoxybutanoyl)pyrrolidine-2-carboxamide 
 (2S)-1-[(2S)-2-[acetyl(methyl)amino]-3-phenyl-butanoyl]-N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-N-methyl-pyrrolidine-2-carboxamide 
 (2S)-1-[(2S)-2-[acetyl(methyl)amino]propanoyl]-N-[(1S)-1-[[(1 S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-N-methyl-pyrrolidine-2-carboxamide 
 (2S)-1-[3-[acetyl(methyl)amino]propanoyl]-N-[(1S)-1-[[(1S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-N-methyl-pyrrolidine-2-carboxamide 
 (2S)-1-[(2S)-2-[[2-[butanoyl(methyl)amino]-3-(1H-indol-3-yl)propanoyl]-methyl-amino]-4-methyl-pentanoyl]-N-[(1S)-1-[[(1 S)-3-[(3,5-difluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-N-methyl-pyrrolidine-2-carboxamide 
 (2S)—N-[(1S)-1-[[(1S)-3-benzamido-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-N-methyl-1-hexanoyl-pyrrolidine-2-carboxamide 
 (2S,4R)—N-[(1S)-1-[[(1S)-3-benzamido-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methyl-butyl]-4-fluoro-N-methyl-1-pentanoyl-pyrrolidine-2-carboxamide 
 or a pharmaceutically acceptable salt, or isomer thereof. 
 
     
     
       11. Pharmaceutical compositions comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier, adjuvant or vehicle. 
     
     
       12. A method for treatment of epilepsy, schizophrenia, Alzheimer disease, autism, mental retardation, bipolar disorders, mood disorders depression, vascular diseases, inflammatory diseases, drug addiction, neuropathic pain, lung diseases, cancer and sepsis wherein a therapeutic amount of the compound according to  claim 1  is administered to a patient in need of said treatment. 
     
     
       13. The method of  claim 12 , wherein the autism is associated to fragile X syndrome. 
     
     
       14. The method of  claim 12 , wherein the mood disorders are bipolar disorders. 
     
     
       15. The method of  claim 12 , wherein the vascular diseases are selected from the group consisting of ischemic stroke and atherosclerosis. 
     
     
       16. The method of  claim 12 , wherein the inflammatory diseases are selected from the group consisting of multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. 
     
     
       17. The method of  claim 12 , wherein the lung diseases are selected from the group consisting of asthma and chronic obstructive pulmonary disease.